Obesity and its related diseases are the most costly health issue facing the US. G protein coupled receptor (GPCR) pathways directly and indirectly control metabolic rate and feeding behaviors that influence the onset of obesity and its related diseases;type II diabetes, cardiovascular disease, metabolic syndrome and nonalcoholic steatohepatitis (NASH). Excess body weight is acquired via daily imbalances in energy input and expenditure. Researchers agree that dietary sugar leads to inhibition of fatty acid oxidation in liver and subsequent hepatic fat accumulation and body weight gain. Much is known about glucagon regulation of liver metabolism, but an entire G protein pathway controlling fatty acid oxidation in liver has been overlooked. We present preliminary data that strongly implicate a Regulator of G protein Signaling (RGS) protein as a missing component of G protein signaling in liver. RGS proteins accelerate GTP hydrolysis on Ga subunits of the Gq/11 and Gi classes, and thereby inhibit signaling. We found an RGS gene that is regulated in liver by feeding and high simple-carbohydrate diets. Over expression of the RGS gene in liver causes fatty liver. A comparable phenotype is observed in knockout mice with a liver-specific deletion of Gq/11. Our hypothesis is that Gq/11 signaling promotes fatty acid oxidation during fasting, and that dietary carbohydrates inhibit fatty acid oxidation by inducing RGS gene expression, mRNA stability, protein translation, and Gq-GAP activity. We propose 3 aims to test this hypothesis. In Aim 1, we will make a liver specific-deletion of the RGS gene to determine if it is necessary, as well as sufficient, to regulate glucose and fatty acid metabolism in liver. Aim 1 will also determine if dietary glucose up regulates RGS GAP activity. In Aim 2, we will identify and characterize the transcription factors that are required for RGS gene expression in liver when mice consume simple carbohydrates. We will characterize RGS gene transcription by nuclear run-on assays, gel-shift (EMSA), promoter deletion analysis, and chromatin immunoprecipitation (ChIP). In Aim 3, we will determine how glucose regulates RGS mRNA stability and protein translation by deletion analysis of the 3'UTR and identification of interacting microRNAs that control liver metabolism. Results from experiments described in this application on the role of RGS in fatty acid oxidation could lead to novel drugs for the treatment of feeding and metabolic diseases.